Tauopathies are a group of nineteen known debilitating neurodegenerative disorders that affect nearly eight million people in the United States. Currently, there is no cure for tauopathies, and there are temporary and limited benefits to current therapeutic strategies. The endoplasmic reticulum (ER) stress sensor PERK (protein kinase R-like ER kinase) has been identified as a participant in the pathogenesis and progression of tauopathies. However, the mechanism by which the PERK pathway causes neuronal dysfunction is still unknown. The long-term goal is to better understand the mechanism(s) that induce(s) neuronal dysfunction in tauopathies, and the overall objective is to determine the mechanism by which tau and PERK synergize to induce neuronal dysfunction. The central hypothesis is that tau and PERK engage in a pathological cycle whereby aberrant accumulation of tau chronically activates PERK, and active PERK activates enzymes that contribute to the production of pathogenic tau. The overall consequence of this cycle is potentiation of tau pathogenic pathways as well as chronic inhibition of protein synthesis. Characterizing the role of the PERK pathway in neuronal dysfunction will identify novel, urgently needed therapeutic targets for tauopathies. The hypothesis will be tested in three specific aims. Aim 1 is designed to determine the extent to which the PERK pathway causes neuronal dysfunction in tauopathies. Aim 2 is designed to determine the mechanism by which PERK activity modulates tau pathology. Finally, Aim 3 will determine the extent of PERK pathway activation in a newly described tauopathy called Primary Age-Related Tauopathy (PART). In Aim 1, we will use pharmacologic and genetic approaches to inhibit PERK in in vivo, in situ, and in vitro models of tauopathy; neuronal function will be measured by cognitive tests, a novel and non-invasive imaging approach called manganese-enhanced MRI, and electrophysiological measurements. Secondly, we will use biochemical, immunohistochemical, and gene expression assays to determine the extent of PERK activity. In Aim 2, we will use pharmacologic and genetic approaches to activate and inhibit PERK in in vivo and in vitro models of tauopathy; we will measure changes to pathological tau and the PERK pathway. Finally, in Aim 3, we will measure changes in the levels of PERK pathway markers and pathological tau in PART CSF and brain parenchyma. This will be the first extensive biochemical approach to PART, which could unveil novel biomarkers of the disease. The identification of a pathogenic PERK-tau cycle is innovative because it departs from the status quo by identifying an effector of disease (PERK) that can cause neuronal dysfunction (downstream) while also potentiating tau aberrancies (upstream). Therefore, the PERK pathway offers a unique repertoire of novel therapeutic targets that can modulate disease in multiple aspects. This approach is significant because of the central role the pathway plays in disease, and therefore, the potential to offer therapeutic solutions to tauopathies.